Local consolidative therapy with surgery and/or radiation has been proven to prolong survival for patients with oligometastatic (i.e., three or fewer metastases) non–small cell lung cancer (NSCLC), but whether patients with a greater metastatic burden would also benefit is not known. The answer may be found in two new clinical trials combining local consolidative therapy with novel systemic treatments to combat metastatic NSCLC.
In the two trials, patients first receive the immune checkpoint inhibitors nivolumab and ipilimumab (LONESTAR trial) or the tyrosine kinase inhibitor osimertinib (NORTHSTAR trial). Patients then are randomly assigned to receive maintenance therapy with the study drug(s) or local consolidative therapy followed by maintenance therapy.
“We’ve shown that local consolidative therapy benefits NSCLC patients with oligometastatic disease, and now we’re expanding the paradigm to include patients who have polymetastatic disease,” said Daniel Gomez, M.D., an associate professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center. “Our hope is that the combination of local consolidative therapy and immunotherapy or osimertinib can extend survival for patients with metastatic disease anywhere in the body.”
Building on promising findings
Dr. Gomez and his colleagues hope that the combination of local consolidative therapy and immune checkpoint inhibitors or the third-generation EGFR (epidermal growth factor receptor) inhibitor osimertinib will extend survival for patients with metastatic NSCLC beyond what has been seen in studies of each modality separately.
The survival benefit of local consolidative therapy was demonstrated in a recent phase II trial (No. 2012-0618) in which patients with oligometastatic NSCLC received first-line therapy and were then randomly assigned to receive local consolidative therapy or maintenance therapy. The median progression-free survival duration of the patients who received local consolidative therapy (11.9 months) was significantly longer than that of patients who received maintenance therapy only (3.9 months; P = .0054).
“This was the first randomized controlled trial to establish that local consolidative therapy slows disease progression in NSCLC patients with limited metastatic disease,” said Dr. Gomez, the trial’s principal investigator.
Immune checkpoint inhibitors also have been shown to benefit patients with metastatic disease. The PD-1 (programmed cell death protein 1) inhibitor nivolumab is approved by the U.S. Food and Drug Administration (FDA) for treating several types of cancer, including previously treated metastatic NSCLC. Furthermore, the combination of nivolumab and the CTLA-4 (cytotoxic T lymphocyte antigen 4) inhibitor ipilimumab—already approved by the FDA for treating metastatic melanoma—is under investigation for the treatment of metastatic NSCLC in a clinical trial (No. 2016-0223). The EGFR inhibitor osimertinib has also shown promise against NSCLC. In March 2017, the FDA approved osimertinib for the treatment of patients with metastatic NSCLC and EGFR T790M mutations.
“One of the main gatekeepers of resistance to EGFR inhibitors is the T790M point mutation,” Dr. Gomez said. “It’s been shown that patients who develop resistance that way can then be treated with osimertinib and the disease responds.”
New clinical trials
“The NORTHSTAR and LONESTAR trials are different from our previous trials of local consolidative therapy because we use novel agents and also because we include not just patients who have oligometastatic disease but also patients who have polymetastatic disease,” Dr. Gomez said. Both trials recently began enrolling patients with metastatic NSCLC.
Dr. Gomez is MD Anderson’s principal investigator of the multi-institutional NORTHSTAR trial (No. 2017-0228), which is enrolling patients with previously untreated or recurrent stage IIIB or IV NSCLC that is not amenable to potentially curative treatment. Treatment-naïve patients must have tumors that harbor an EGFR exon 19 deletion or L858R mutation, whereas patients with recurrent disease must have an EGFR T790M mutation that arose during treatment with an EGFR inhibitor such as erlotinib, gefitinib, or afatinib. Patients previously treated with osimertinib or another third-generation tyrosine kinase inhibitor are not eligible for the trial.
All patients in the trial receive osimertinib for 6–12 weeks. Those whose disease does not progress during this induction therapy are then randomly assigned to receive osimertinib maintenance therapy only or local consolidative therapy followed by osimertinib maintenance therapy. All patients will continue the maintenance therapy until disease progression or unacceptable toxic effects occur. Dr. Gomez and his colleagues will compare progression-free survival between patients who received local consolidative therapy and patients who did not.
The LONESTAR trial (No. 2017-0311) is enrolling patients with stage IV NSCLC who are treatment naïve or have undergone one line of chemotherapy or targeted therapy. Patients whose disease is classified as adenocarcinoma must have wild-type EGFR and ALK; patients with other NSCLC subtypes do not need to be tested for EGFR or ALK status because such mutations are rare in these subtypes. Patients who have undergone systemic immunotherapy for their disease are ineligible for the trial.
All patients receive two 6-week cycles of nivolumab and ipilimumab. Then, patients whose disease has not progressed are randomly assigned to receive maintenance therapy only with nivolumab and ipilimumab or local consolidative therapy followed by maintenance therapy with nivolumab and ipilimumab. All patients will continue maintenance therapy for up to 2 years.
The principal investigator of this MD Anderson–only trial is John Heymach, M.D., Ph.D., a professor in and chair of the Department of Thoracic/Head and Neck Medical Oncology. The trial’s co-principal investigators are Dr. Gomez and Stephen Swisher, M.D., a professor in the Department of Thoracic and Cardiovascular Surgery and head of the Division of Surgery. The researchers will compare overall and progression-free survival between patients who received local consolidative therapy and those who did not.
Determining local consolidative therapy
In both the NORTHSTAR and LONESTAR trials, a multidisciplinary treatment team determines the approach for local consolidative therapy. Whether a patient should be treated by surgery, radiation, or both depends on tumor location and extent of disease. In most patients, the same modality is used to treat all lesions, but some patients are better suited for a hybrid approach in which some lesions are resected and others irradiated.
“Certain lesions tend to be better suited for surgery versus radiation therapy,” Dr. Gomez said. “We prefer to use surgery for lung lesions that can be resected with a lobectomy, for a single brain metastasis or a dominant brain metastasis, and for some adrenal gland lesions that can be resected with relatively modest risk. Other metastases are generally treated with radiation.”
The surgeons and radiation oncologists use whichever surgical and radiation techniques are most likely to achieve treatment goals. Lung lesions may be resected by open thoracotomy or video- or robot-assisted thoracoscopy/laparoscopy; the goal for all resections is grossly negative surgical margins. For radiation therapy, stereotactic body radiation therapy is the most common modality used, although modalities such as intensity-modulated radiation therapy and proton therapy are available. The goal of radiation therapy is to ablate the disease.
“Whether we use surgery or radiation, the main point is to be aggressive,” Dr. Gomez said. “We think treating as many lesions as possible is the key to prolonging survival for patients with metastatic NSCLC.”
Gomez DR, Blumenschein GR, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multi-centre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17:1672–1682.
Skoulidis F, Papadimitrakopoulou VA. Targeting the gatekeeper: osimertinib in EGFR T790M mutation–positive non–small cell lung cancer. Clin Cancer Res. 2017;23:618–622.
OncoLog, March 2018, Volume 63, Issue 3